Several devices and pharmaceutical compositions are available for the prevention of undesirable conception in the case of regular sexual activity. Condoms, pessaries, intrauterine devices as well as different mono or multi-phasic oral contraceptives are some examples of contraceptives that are effective in preventing unwanted conception.
However, in the case of unprotected sexual intercourse, coitus with imperfect contraception (for example, a damaged or torn condom) or possibly victims of rape, action must be taken to prevent conception, soon after exposure. Emergency contraception is a method of preventing pregnancy post-coitus.
Ovulation results from a cascade of events including but not limited to releases of hormones, activation of transcription mechanisms as well as physiological changes. A surge of luteinizing hormone (LH) commences the process of ovulation. The pinnacle of ovulation is the follicle rupture and release of an oocyte from the ovary. After release of the oocyte, well-defined and vascularized structures form in the ovary from the encasement (differentiated thecal and granulosa cells) of the oocyte termed the corpora lutea. This structure releases the hormone progesterone.
The use of levonorgestrel in emergency contraception was discovered a few decades ago. The results of the studies were reported in two well-documented publications [Lancet 1998; 352: 428-33, and Ho, et al., Human Reproduction 8(3): 389-92 (1993)]. The efficacy of tablets containing only 0.75 mg of levonorgestrel and the combined tablets of the Yuzpe method containing 0.1 mg of ethinyl-estradiol+1.0 mg levonorgestrel were studied by administering the doses 12 hours apart within 48 as well as within 72 hours of unprotected coitus. The results showed that protection with two tablets containing 0.75 mg of levonorgestrel was better than with the Yuzpe regimen, but the women, who received only levonorgestrel, observed less side effects, which could be due to the lack of ethinyl-estradiol.
The mechanism of action of levonorgestrel used as postcoital contraceptive was investigated in several studies. Keserü, et al., Contraception 10(4):411-24 (1974), report that the anti-ovulatory effect probably depends partly on the time elapsed between talking the last tablet and the time of ovulation, partly on the quantity of the applied hormone. According to other authors, factors other than the inhibition of ovulation can also influence the contraceptive effect [Hapangama, et al., Contraception 63:123-29 (2001)]. Levonorgestrel administered in the follicular phase decreased the proliferation activity of the endometrium, while in the luteal phase there was no effect [Landgren, et al., Contraception 39(3):275-89 (1989)].
Several trials were conducted to show the effect of levonorgestrel on the cervical mucus, which could be observed a few hours after the administration. Levonorgestrel inhibits the sperms getting into the upper genital tract in such a way that it causes the thickening of the cervical mucus almost immediately after the absorption of the hormone. It was also shown that after the administration of 400 μg of levonorgestrel the alkalization of the intrauterine fluid starts already after 4 hours of administration and it lasts for approximately 48 hours. This effect can play a role in the inhibition of the movement of sperms and their entry into the uterine cavity, and as a consequence, in the contraceptive effect as well [Spona, et al., Contraception 11(1):31-43 (1975)].
The studies showed that two pharmaceutical compositions containing 0.75-0.75 mg of levonorgestrel used at 12 hours' interval within 72 hours after the unprotected coitus successfully inhibited the conceptions which otherwise might have occurred. The efficacy was significantly better than the efficacy of the Yuzpe regimen used worldwide earlier. Because of the lack of the estrogen component, side effects (nausea, feeling of sickness, vomiting) leading to the decrease in compliance and the efficacy of the treatment were observed far, less frequently. The results of the clinical studies showed that the efficacy was the better the earlier the treatment started after the coitus. However, according to experience, if women wanted to follow the instructions correctly, they often delayed taking the first tablet so as taking the second dose after 12 hours would not fall on an extremely inconvenient time (for example 3 o'clock in the morning). The results of the studies showed that the prescription of the 12 hour interval between the two doses decreased the compliance. According. to statistical data, the majority of women took the second dose within 12 to 16 hours after the first one [Lancet 1998; 352: 428-33]. More recently, a study from the WHO showed that intake of the 2 doses at the same time did not differ in efficacy as compared with the 2 doses taken 12 h apart, and therefore this newly proposed single dose regimen would have a better acceptability for EC use [von Hertzen, et al., Lancet 360:1803-10 (2002)].
In Ortiz, et al., Hum. Reprod. 19(6):1352-56 (2004), it was concluded that levonorgestrel exerts its EC effect by inhibiting or delaying ovulation.
Mifepristone (RU-486) has been used as an emergency contraceptive by inhibiting ovulation. Sarkar, Acta Obstet Gynecol Scand 84(4):309-16 (2005), describes the potential of RU-486 as an emergency contraceptive drug. Post-coital contraceptive pills are also disclosed in U.S. Pat. No. 4,670,426, and which contain a progesterone antagonist such as RU-486 and a blocker of estrogen synthesis. Gemzell-Danielsson et al., Hum. Reprod. Update 10(4):341-8 (2004), describes the mechanisms of action of mifepristone and levonorgestrel when used for emergency contraception.